3-substituted 2-oxindole-1 carboxamide pharmaceutical compositions

ABSTRACT

The present invention relates to a pharmaceutical preparation comprising: (A) at least one triglyceride or propylene glycol diester of fractionated coconut oil fatty acids; and (B) at least one carboxamide compound of the formula I. The composition renders the carboxamides of formula I more storage-stable and less susceptible to hydrolysis. Methods of using the composition to inhibit activation of collagenase, treating inflammatory disease, and eliciting an analgesic response are also disclosed.

This is a continuation, of application Ser. No. 08/416,721, filed onApr. 6, 1995, abandoned.

BACKGROUND OF THE INVENTION

This invention relates to pharmaceutical compositions comprising certain3-substituted 2-oxindole-1-carboxamides and medium chain (C₈ to C₁₀)fatty acid triglyceride and propylene glycol diesters. Thesecarboxamides are useful as analgesics for use in mammals such as man andin ameliorating or alleviating pain encountered while recovering fromsurgery or other trauma or in eliminating the symptoms of chronicdiseases such as inflammation and pain associated with rheumatoidarthritis and osteoarthritis, as shown in U.S. Pat. Nos. 4,556,672 and5,047,554. The carboxamides are also useful for treating collagenasemediated disorders and diseases, such as bone resorption disorders,corneal ulceration, periodontal disease, inflammatory diseases, andwounds of the skin and burns in a mammal, as shown in U.S. Pat. No.5,008,283.

The carboxamides described in formula I are chemically unstable inwater. It is known that the rate of hydrolytic degradation may bereduced by protection of labile drugs e.g. sequestration in thehydrophobic core of micelles or formulation in low water activity,non-aqueous solvent-based vehicles i.e. essential oils. In addition tohydrolytic instability the carboxamides are also prone to oxidativedegradation in aqueous e.g. water, and non-aqueous e.g. oils, vehicles.Oxidative instability can be reduced in saturated oils by inclusion ofantioxidants or by formulation in unsaturated oils which protect thedrug by being preferentially oxidized themselves. However, thecarboxamides described in formula I are not readily stabilized in oilscommonly used in pharmaceutical preparations e.g. sesame oil, peanutoil, safflower oil, cottonseed oil.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical preparationcomprising:

(A) at least one triglyceride or propylene glycol diester offractionated coconut oil fatty acids; and

(B) at least one compound of the formula ##STR1##

where R₁, R₂, and R₃ are each independently hydrogen, fluoro, bromo, orchloro, or a pharmaceutically acceptable salt thereof,

wherein the weight ratio of (A) to (B) ranges from 5.6 to 999.

The pharmaceutical preparation includes 85 to 99% by weight of (A) and0.1 to 15% by weight of (B).

Preferably, R₁, R₂, and R₃ are each independently fluoro or chloro.

Preferred compounds of formula I include:

5-chloro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl)-indole-carboxamide;

6-chloro-5-fluoro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl)-in-dole-carboxamide;and

6-chloro-5-fluoro-2,3-dihydro-2-oxo-3-(2-(4-chloro)-thienyl-carbonyl)-indole-carboxamide.

The present invention also includes a method of inhibiting activation ofcollagenase.

The present invention also includes a method of treating an inflammatorydisease.

The present invention also includes a method of eliciting an analgesicresponse.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that pharmaceutical preparations including thecarboxamides of formula I and C₈ to C₁₀ saturated fatty acidtriglycerides and propylene glycol diesters have superior productviability and shelf life. As the result of utilizing such a formulation,the carboxamides are less susceptible to hydrolysis and oxidation whichcan deteriorate them and ultimately render them ineffective.Stabilization of the carboxamides in these preparations do not requirethe addition of an antioxidant or other auxiliary stabilizers.

The triglycerides used in the claimed invention are neutral oils whichare composed of esters of medium chain (C₈ to C₁₀) fatty acids, alsoreferred to as fractionated coconut oil. These fatty acids areesterified with either glycerin or propylene glycol and are sold underthe name MIGLYOL® (i.e. MIGLYOL® 810, MIGLYOL® 812, and MIGLYOL® 840).MIGLYOLS are also described as triglycerides of fractionated coconut oilfatty acids or caprylic acid/capric acid triglycerides. Fractionatedcoconut oil is prepared from the fixed oils obtained from the driedsolid part of the endosperm of Cocos nucifera L by hydrolysis,fractionation of the liberated fatty acids and re-esterification withglycerol or propylene glycol. It consists of a mixture of short andmedium-chain saturated fatty acids, mainly octanoic and decanoic acids.Miglyol® is the trade name for fractionated coconut oil or caprylicacid/capric acid triglycerides from Dynamit Nobel Ltd., Germany and theU.K. These vehicles have demonstrated stability against oxidation andrancidification as well as outstanding safety and biocompatibility.Furthermore, since only saturated fatty acids are used the oils do notgenerate peroxides or other free radicals which could destabilize thepharmaceutical contained therein. The low water content also minimizesthe hydrolysis of the carboxamide. In the preferred composition, acarboxamide of formula I is dispersed in an oil vehicle comprisingMiglyol® 812 and other oil-soluble additives described below underagitation to produce a homogenous suspension of the drug substance inthe oil vehicle.

Other additives which can be present in the pharmaceutical preparationcan include an anticaking agent such as, for example, propylene glycol,polyethylene glycol, glycerin, sorbitol, benzyl alcohol, lecithin, oraluminum stearate. The amount of anticaking agent can range fromapproximately 0.05 to 5% by weight. The pharmaceutical preparation canalso contain preservative in an amount ranging from 0.5 to 2.0% byweight. Such preservatives can include, for example, phenol, benzylalcohol, parabens, chlorbutanol, and benzyl benzoate. Gelling agents,such as aluminum monostearate can also be included in the pharmaceuticalpreparation in an amount ranging from 0.5 to 3.0% by volume.

The stability of these pharmaceutical preparations can be evaluated, forexample, under accelerated storage conditions after subjectingsuspensions of the carboxamides (6% by weight of the drug substance)packaged in glass vials to high temperatures of up to 70° C. for up tonine weeks. During the stability challenge the level of intact drugremaining in the preparation, as well as hydrolytic and oxidativedecomposition products is quantified by high performance liquidchromatography (HPLC). For assay, the suspension is diluted withmethanol/triethylamine 100/1 volume-by-volume to give a final drugconcentration of 0.6 to 1.2 mg/mL. This solvent dissolves the suspendeddrug to produce a solution which can be directly injected on the HPLCcolumn. For chromatography, the mobile phase is methanol/water 90/10 v/v+1% triethylamine, the column is a reversed phase octadecasilane and thesolvent flow rate was 1 mL/minute. Drug detection was by UV absorbanceat 246 nm. Such an assay has shown there to be virtually nodecomposition of carboxamide in suspension after nine weeks.

When a compound of formula I or salt thereof is used in a human subject,the daily dosage will normally be determined by the prescribingphysicians. Moreover, the dosage will vary according to the age, weightand response of the individual patient, as well as the severity of thepatient's symptoms and the potency of the particular compound beingadministered. However, for acute administration to relieve pain, aneffective dose in most instances will be 0.01 to 0.25 g as needed (e.g.,one- to four-times-a-day). For chronic administration, in most instancesan effective dose will be from 0.01 to 0.5 g per day, and preferably 0.1to 0.25 g per day in single or divided doses. On the other hand, it maybe necessary to use dosages outside these limits in some cases.

Preferably the pharmaceutical compositions of the present invention areparenteral pharmaceutical compositions. The pharmaceutical compositionsof this invention may be produced by formulating a compound of formula I(as the active ingredient) in dosage unit form. Some examples of dosageunit forms are sterile suspensions for intramuscular, subcutaneous orintra-articular injection, sterile ophthalmic suspensions for topicalapplication to the eye, capsules for oral administration, rectalsuppositories, or topical lotion for application to the skin or scalp.

An example of a suitable pharmaceutical dosage for oral administrationare soft gelatin capsules. Orally administered suspensions can bedelivered, e.g., upon encapsulation of a suspension of compound I in theoil, i.e. Miglyol 812, in a soft gelatin capsule. A rectal suppositorymay be formulated by dispersing the carboxamide in a neutral oil alongwith compatible suppository bases, such as cocoa butter or WhitepsolW35, which have melting points above body temperature. A topical productfor application to the skin would contain the carboxamide as the activeagent dispersed in the neutral oil, e.g., Miglyol 812, and alsocontaining one or more pharmaceutical inactive ingredients, such as:cetyl alcohol, stearic acid, propylene glycol, aluminum monostearate,benzyl alcohol, as diluents and preservatives. A parenteral compositionis preferably a suspension of the carboxamide in the neutral oil, andmay also contain other inactive pharmaceutical components, such as:benzyl alcohol as preservative, aluminum monostearate as a gelling agentand propylene glycol as a dispersing agent.

The following Example illustrates how the pharmaceutical preparationscan be prepared. Commercial reagents can be utilized without furtherpurification.

EXAMPLE 1

800 mL of Miglyol 812 was heated to 45° C. in a compounding vesselequipped with an agitator and homogenizer. 10 g of benzyl alcohol wasadded to the oil under agitation (about 60-80 R.P.M.). The oil solutionwas sterile filtered into a sterile compounding vessel equipped wait anagitator and homogenizer. 120 g of micronized, sterile carboxamidepowder was dispersed into the oil phase under agitation. The suspensionwas homogenized under high shear for ten minutes and then was allowed tocool to room temperature under mild agitation (60-80 R.P.M.). Thesuspension was brought to a total batch weight of 1000 grams with theaddition of the required amount of sterile Miglyol 812 to the suspensionto give a final concentration of 12% by weight of carboxamide in thefinal formulation. The suspension was aseptically filled into 50 cc,Type I, flint glass vials using an automated filling apparatus. Thevials were capped with teflon-coated rubber stoppers and crimped withaluminum shells.

EXAMPLE 2

800 mL of Miglyol 812 was heated to 45° C. in a compounding vesselequipped with an agitator and homogenizer. 10 g of benzyl alcohol wasadded to the oil under agitation (⁻ 60-80 R.P.M.). The oil solution wassterile filtered into a sterile compounding vessel equipped with anagitator and homogenizer. 20 g of sterile, aluminum monostearate powderwas added to the oil solution in divided portions under agitation to gelthe oil. The gelled oil was allowed to cool to room temperature andallowed to stand for six hours without agitation. 120 g micronized,sterile carboxamide powder was then dispersed into the gelled oil underagitation. The suspension was brought to a total batch weight of 1000grams with the addition of the required amount of sterile, gelledMiglyol 812 to the suspension to give a final concentration of 12% byweight of carboxamide in the final formulation. The suspension wasaseptically filled into 50 cc, Type I, flint glass vials using anautomated filling apparatus. The vials were capped with teflon-coatedrubber stoppers and crimped with aluminum shells.

EXAMPLE 3

800 mL of Miglyol 812 was heated to 45° C. in a compounding vesselequipped with an agitator and homogenizer. 10 g of benzyl alcohol wasadded to the oil under agitation (about 60-80 R.P.M.). 120 g ofmicronized, sterile carboxamide powder was dispersed into the oil phaseunder agitation. The suspension was homogenized under high shear for tenminutes and then was allowed to cool to room temperature under mildagitation (60-80 R.P.M.). The suspension was brought to a total batchweight of 1000 grams with the addition of the required amount of Miglyol812 to the suspension to give final concentration of 12% by weightcarboxamide in the final formulation. The suspension was filled intosoft gelatin capsules using an automated filling apparatus for oralingestion.

EXAMPLE 4

200 g of Miglyol 812 and 800 g of Whitepsol W35 were heated to 60° C. ina compounding vessel equipped with an agitator and homogenizer.Carboxamide powder was dispersed into the resulting oil solution underagitation. The suspension was allowed to filled into suppository moldsand congealed by cooling to room temperature.

I claim:
 1. A pharmaceutical preparation comprising:(A) at least onetriglyceride or propylene glycol diester of fractionated coconut oilfatty acids, wherein said coconut oil fatty acids include C₈ to C₁₀fatty acids; and (B) at least one compound of the formula ##STR2## whereR₁, R₂, and R₃ are each independently hydrogen, fluoro, bromo, orchloro, or a pharmaceutically acceptable salt thereof, wherein the ratioof % by weight of (A) to % by weight of (B) ranges from 5.6 to
 999. 2.The pharmaceutical preparation of claim 1, wherein the compound offormula I is5-chloro-2,3-dihydro-2-oxo-3-(2-thienyl-carbonyl)-indole-carboxamide. 3.The pharmaceutical preparation of claim 1, wherein said coconut oilfatty acids comprises caprylic acid, caproic acid, lauric acid, andlinoleic acid.